CA1165239A - Vaginal ring - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A vaginal ring comprises a supporting ring free of active agent. A layer, which contains an active agent such as a steroid, is applied on its outer rim, optionally in a continuous groove provided in the supporting ring. This layer, in turn, is coated with a layer devoid of active ingredient. All components pre-ferably comprise an LTV silicon elastomer. The ratio of the thickness of the layer, containing an active agent, to the layer, free of active agent, is about 5-50 : 1. As a result, a long-term and uniform release rate is achieved for the active agent.

Description

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T,he present invention relates to vaginal rings.
Vagi,nal rings com~osed of synthetic resins, and contain-ing active ingredients, have been known for some time. D~S

2,450,107 and its U.S. equivalent 4,012,496 describe a vaginal ring consisting o~ a supporting ring with one or two continuous pocket-like indentations adapted to accommodate active-agent-containing rings which;fit into these ~ndentations and are made of a synthetic LTV silicone elastomer resin. U.S. Patent

3,920,805 l,ikewise describes a vaginal ring of a silicone elastomer consisting of a core free of active agent and a coating containing an active agent. Both systems have in common that the active ingredient is released directly to the surrounding body parts from the part containing the active agent. However, an-nular devices are likewise conventional wherein the part con-taining the active agent is coated with a diaphragm free of active ingredient (U.S. Patent 3,854,480). In this device, the annular core consists of a silicone elastomer containing an active agent, encompassed by a polyethylene hose having a wall thickness of about 0.8 mm. The conventi'onal vaginal rings, howqver, are disadvantageous in that the release rate over the desired time period is not constant. Rather, the amount per unit time becomes lncreasingly smaller after an initial surge of active agent.
Acoordingly, the present invention provides a vaginal ring having a release of active agent which is of uniform regu-larity and of long duration.
According to the present invention there is provided in a vaginal ring comprising a pharmacologically acceptabe supporting ring essentially free o~ medicament, and on its outer rim ~ first conti,nuously encircling pharmacologicall~ acceptable layer which contains a pharmacologically active agent, the improvement uherein, said first layer is coated with a second pharmacologically 1~65Z;;3~

acceptable layer which is essentially medicament free but which is permeable to the active agent in the first layer; the ratio of the thickness o-f the first layer to that of the second layer being about 5-50:1.
The present invention will be more fully described by way of the accompanying drawings, in which like reference charac-ters designate the same or similar parts throughout the several views, and wherein~ -Figure I schematically illustrates a top view of a vaginal ring of this invention;
FiguresIIand III show a section A-B of two embodiments of such a ring; and Figure IV shows the uniformity of release of active agent from a vaginal ring of this ~invention. (Release per day over a time period of more than 2 months).
Thus in accordance with the present invention the va-ginal ring comprisés a supporting ring 1 ree of active agent;
a layer 2 applied to its outer rim and containing an active steroid agent; a layer 3 devoid of active agent coated onto layer 2; wherein the ratio of the thicknesses of the layer 2, containing an active agent, and the layer 3, free of active agent, is about 5-50 : 1. The supporting ring 1 can have a continuous groove to accomodate the layer 2.
The vaginal ring of this invention has an average outer dimension of 0.5-20 cm, the exact size being dependent on the particular application. In the case of relatively small mammals, such as dogs, the ring size will be smaller than in the case of relatively larger mammals, such as horses or cows. For Rhesus monkeys, for example, the outer diameter is about 2-3 cm. In vaginal rings for human females, the outer diameter is about 5-7 cm and the largest width of the ring cross section (See, e.g., Section A-~ of Figures I to III) is 5-10 mm. Dimensional details 1165Z~9 for any ring for any applic~at~on can be conventionally deter-mined, ~f nece~sa;ry, using routine ~rel`iminary experiments.
In a ~pecial embodiment of the supporting ring 1, a groove is contained i~n ~ts outer ~m ~or engaging layer 2, (see, e.g., Figure III as weIl as other Variants shown in U.S.
Patent 4,012,4~6~.
Unless indicated other~se hexein, all details of all aspects o~ this invention are fully conventional and can be determined by analogy to th~se of U.S. Patent 4,012,496.
10 . Such details includebut are not limited to chemical compo-sitions of the layers, active drugs, overall sizes and shapes, cross-sectional sizes and shapes of the ring and individual ring components, methods of construction and preparation of each ring component, etc.
In a special embodiment of the invention the vaginal ring has an outer diameter of 58 to 60 mm, an inner diameter of 50 to 52 mm, and the largest width of the non-circular cross-section ~see, e.g., section A-B of Fig. II or III) is 6.5 to 7.5 mm.
The supporting ring 1 comprises a physiologically acceptable synthetic resin, such as, for example, polyethylene, RTV silicone elastomers, LTV silicone elastomers, polyamides, and polytetrafluoroethylene. An especially suitable synthetic resin is LTV silicone elastomer whose vulcanization behavior with respect to the layer 2 containing the active ingredient does not cause any technical problems.
~ preferred LTV silicone elastomer has the following composition:
8Q - 98% by we~ght of polydimethylvinylsiloxane 1 ~ lQ~ by we~ght of tetramethyltetravinylcyclotetrasiloxane 2 ~ 20% by we~ght of polyd~methyl hydrogen siloxane .

~65Z~9 0.5 ~ 10% by weight of highly disperse silicic acid;
and;
10 - 10Q pPm of platinum catalyst.
Suitable platinum catalysts include metallic platinum per se, platinum on support materials, such as silica gel, or platinum in the form of its salts, e.g., pla~inum carbonyl ai-chloride or platinum dicarbonyl dichloride, or as hexachloro-platinic acid. Also suitable are platinum complexes of unsatura-ted siloxanes (cf. European Laid Open ~pplication 000 2744).
The composition for producing the supporting ring can optionally also contain, in addition to highly dispersed silicic acid, which influences primarily only the mechanical properties, also other auxiliary materials, such as, for ex-ample, tensides, solubilizers, colori-ng agents, etc., as long as they are inert with respect to the total system.
The layer 2 containing the active agent comprises as a base composition, a pharmaceutically acceptable resin from which the agent can be released, e.g., as described in U.S. Patent

4,012,496. Especially preferred is a combination of drug and L~V

silicon elastomer, particularly one of the following composition:
75 - 98% by weight of polydimethylvinylsiloxane 1 - 10% by weight of tetramethyltetravinylcylco-tetrasiloxane 1 - 10% by weight of polydimethyl hydrogen siloxane 10 - 100 ppm of a platinum catalyst, and 1 - 10% by weight of active agent.
Suitable active agents are any of those for which ad-ministration is possible by a vaginal ring and which are compati-ble with the system and methodology of this invention. Especially suitable as active agents are those which are nonionic and lipid-soluble, especially steroid hormones having a progestational orestrogenic ac~ivity. Examples in this connection are ethynyl-estradiol, ethisterone, norethisterone acetate, norethynodrel, .

~652~9 evonQrgestrel, or gestodene, The laye~ 3, free of active agent, likewise can com-- prise any LT~ s~licone eIastomer. Especially preferred is an LTV siliconeelastomer, particularly one having the following composition:
75 - 98~ by weight o polydimethylvinylsiloxane 1 - 10% by weight of tetramethyltetravinyl-cyclotetrasiloxane 2 - 20~ by weight of polydimethyl hydrogen siloxanè, and 10 - 100 ppm of a platinum catalyst.
The devices of this invention are manufactured according to fully conventional methods such as, preferably, by the injection molding technique for layers 1 and 2.
Specific details for forming any component or overall device of this invention or for forming any composition are fully conventional and can be determined readily from U.S. Patent 4,012,496, for example. All starting materials are known.
For example, the amount of polydimethylvinylsiloxane employed is advantageously fi'rstdivided typically into portion'sof 1:1.
One'portion is usédtogetherwith the polydimethylhydrogen siloxane, and the othertogetherwith the'platinumcatalyst. The twoportionsareco~bined only shortlybefore vulcanization and'are crosslinked bytemperatureincrease~
The active agent is suitably micronized before being incorporated into the liquid mixture of the starting components.
The layer 3, free of activé ingredient, is likewise applied according to methods known per se, such as dipping or spraying using ~ully conventionalprocedures for such techniques.
The layer thickness is generally 10 - 1,000, preferably 100 -500 ~m. The ratio of thickness of layer 2 to layer 3 is 5 - 50:1, preferably 20 - 40:1.
The vaginal ring of this invention has the advantage that the active agent is released over a relatively long period

- 5 1~ 6S2~9 of time within the limits of the d~sage required for the biologi-cal ef~ect desired, e.g~, the dose necessary for inhibition of ovulation, in a regular and unl~orm fashion. The use of the vag~nal rings of this invention ~s fully conventinal including methods and precautions of insertion, maintenance and removal, except, of course that advantage can be taken of the long-term :
and regular drug release provided.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following pre-ferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. In the follwoing examples, all temperatures are set forth uncorrected in degrees Celsius;
unless otherwise indicated, all parts and percentages are by weight.
Example 1 The following components are thoroughly mixed for producing the supporting ring 1 232.577 g of vinyl-terminated polydimethylsiloxane having an average molecular weight of M 5854, 17.423 g of tetramethyltetravinylcyclotetrasiloxane and 25.000 mg of platinum (mixture Al), as well as 193.789 g of vinyl-terminated polydimethylsiloxane and-56.211 g of polydimethyl hydrogen siloxane (mixture Bl) The two mixtures Al and Bl are homogenized in a static mixing pipe, introduced int~ an injection molding tool, and ; vulcanized during a period of 60 seconds at lOO~C into rings having a cross section of a circular segment.
The Shore A hardness is 45, and the el~ngation at rupture is 50%.

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1~65~9 To produce the layer 2, containing the active agent, the follo~in~ components are mixed intensively 4~,86 g~ of vinyl-terminated polydimethylsiloxane (M = 8170) 0.14 g of tetramethyltetravinylcyclotetrasiloxane, 5.00 mg of pla~inum,.and 1.814 g of:levonorgestrel (mixture A2), as well as 48.61 g of vinyl-terminated polydimethylsïloxane -~ ~M = 8170), 101.39 g of polydimethyl hydrogen siloxane, and 1.814 g of levonorgestrel tmixture B2).
The two mixtures A2 and B2 are homogenized in a static mixing pipe, introduced into an injection molding tool with inserted supporting rings 1, and vulcanized onto the outer~rim of the supporting ring 1 for a period of 60 seconds at 100C.
The thus~produced vaginal rings are sprayed, in the region of the layer 2 containing the active agent, with a layer 3 of silicone elastomer having a thickness of about 2ao ~m. This layer forms a composite vulcanizate with the layer 2 disposed 20 therebelow.
The silicone elastomer mixture for the layer 3 free of active ingredient is composed of 42.53 g of vinyl-terminated polydimethylsiloxane (M = 4561), 5.72 g of polydimethyl hydrogen siloxane, 1.75 g of tetramethyltetravinylcyclotetrasiloxane, and ppm of platinum.
Th~ individual ring contains accordingly 0.8% of active ingredient and has a release rate of 70.5 ~g/d.
.. . .. . .
EXample 2 Analogously to Example 1, supporting rings 1 are pro-duced fr~m ~652~9 233 98 g of vinyl-terminated pol~dimethylsiloxane (M = 8170), 16.02 g of tetramethyltetravinylcyclotetrasiloxane, 25.00 mg of platinum, and 13.158 g of highly disperse silicic acid, as well as 203.92 g of vinyl-terminated polydimethylsiloxane (M = 8i70), 46.08 g of polydimethyl hydrogen siloxane, and 13.158 g of highly disperse silicic acid.
The Shore A hardness is 65, and the elongation at rup-ture is 75%.
A layer 2 containing active ingredient is vulcanized onto the supporting rings 1, this layer having the following composition:
239.38 g of vinyl-terminated polydimethylsiloxane (M = 8170), 10.62 g of tetramethyltetravinylcyclotetrasiloxane, 25.00 mg of platinum catalyst.
27.778 g of levonorgestrel, as well as 217.70 g of vinyl-terminated polydimethylsiloxane (M = 8170), 32.30 g of polydimethyl hydrogen siloxane, 27.778 g of levonorgestrel.
Thereafter a layer 3 free of active agent and having a thickness of 350 ~m is applied to the layer 2 containing the active ingredient, this layer 3 having the following composition:
47.061 g of vinyl-terminated polydimethylsiloxane (M = 8170), 0.681 g of tetramethyltetravinylcyclotetrasiloxane, 2,258 g of polydimethyl hydrogen siloxane, and 50 ppm of platinum~
The individual ring contains accordingly 2.3% by weight 1~65~9 of active agent and has a release rate of 45 ~g/d.
- Example 3 The Same blend as set forth in Example 1 is used for producing the supporting ring 1, consisting of polydimethylsilox-ane, tetramethyltetravinylcyclotetrasiloxane, platinum, as well as polydimethyl hydrogen siloxane.
The two mixtures Al and Bl are homogenized in a static mixing pipe, introduced into an injection molding tool, and vul-canized for a period of 60 seconds at 100C into rings having a continuous groove, as shown in Figure III.
Subsequently, a composition containing an active in-gredient, consisting of the two mixtures A2 and B2, Example 1, is injected into the groove and vulcanized for 60 seconds at 100C.
Thereafter, the layer 3, free of active ingredient and having the same composition as in Example 1, is applied to the thus-manufac-tured ring.
The individual ring has an active agent release rate of ~0 ~g/d.
The Vitro release rates (See Fig. IV) are measured as follows: ' The ringis fitted to a support and placed in vessels con-taining 200 ml of double-distilled water. The ring is fixed about 10 mm above the bottom of the vessel which has a diameter of 85 mm and aheight of90mm. After an incubation period of 24 hours at 37~ the levonorgestrelcontaining water is exchanged and analysed.
The levonorgestrel dissolved in the water is concentrated by means of a chromatographic column filled with lipophilized silica gel.
By passing the water through the column the steroid is bound by the aliphatic residues to the surface of the silica gel. The bound stexoid is then removed by elution of the column with 5 ml Gf methanol. The concentration of steroid is determined spectro-photometrically at a wavelength of 248 mm.

~5~9 The preceding examples can be repeated with similar success by subst~tuting the generically or speci~ically described reactants and~or operatin~ conditions of this inVention for those used in the preceding examples..

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Claims (9)

1. THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
   PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
   l. In a vaginal ring comprising a pharmacologically acceptable supporting ring essentially free of medicament, and on its outer rim a first continuously encircling pharmacologically acceptable layer which contains a pharmacologically active agent, the improvement wherein, said first layer is coated with a second pharmacologically acceptable layer which is essentially medica-ment free but which is permeable to the active agent in the first layer; the ratio of the thickness of the first layer to that of the second layer being about 5-50:1.
2. 2. A vaginal ring of claim 1, wherein the thickness of the second layer is 10-1000 µm.
3. 3. A vaginal ring of claim 1, wherein the thickness of the second layer is 100-500 µm.
4. 4. A vaginal ring of claim 2, wherein each of said two layers comprises an LTV silicone elastomer.
5. 5. A vaginal ring of claim 4, wherein the second layer consists essentially of an LTV silicone elastomer of the following composition:
   75 - 98% by weight of polydimethylvinylsiloxane 1 - 10% by weight of tetramethyltetravinyl-cyclotetrasiloxane 2 - 20% by weight of polydimethyl hydrogen sil-oxane, and 10 - 100 ppm of a platinum catalyst.
6. 6. A vaginal ring of claim 5, wherein the supporting ring consists essentially of an LTV silicone elastomer of the following composition:
   80 - 98% by weight of polydimethylvinylsiloxane 1 - 10% by weight of tetramethyltetravinyl-cyclotetrasiloxane 2 - 20% by weight of polydimethylhydrogen siloxane 0,5 - 10% by weight of highly disperse silicic acid, and 10 - 100 ppm of platinum catalyst and the first layer consists essentially of an active agent and an LTV silicone elastomer and has the following composition:
   75 - 98% by weight of polydimethylvinylsiloxane 1 - 10% by weight of tetramethyltetravinyl-cyclotetrasiloxane 1 - 10% by weight of polydimethyl hydrogen siloxane 10 - 100 ppm of a platinum catalyst, and 1 - 10% by weight of active agent.
7. 7. A vaginal ring of claim 1 or 6, wherein the sup-porting ring has a continuous groove in its outer rim which is adapted to mate with the first layer containing the active agent.
8. 8. A vaginal ring of claim 1, wherein the active agent in the first layer is a steroidal progestogen, a steroidal estrogen or a combination thereof.
9. 9. A vaginal ring of claim 8, wherein the active agent is ethynylestradiol, ethisterone, norethisterone acetate, nore-thynodrel, levonorgestrel, or gestoden or a mixture thereof.